1. Field of the Invention
The present application relates to modulating the activity of the immune system using microRNA. More particularly the application relates to modulating immune system development and function through miR-146.
2. Description of the Related Art
Historically, the innate and adaptive arms of the immune response have been represented as two separate systems with distinct properties. However, there are several types of immune cells whose phenotypic features place them at the border of the innate and adaptive systems and provide a bridge between the two. This list includes B1 B cell, marginal zone (MZ) B cells, natural killer T (NKT) cells, γδ T cells and intestinal epithelial lymphocytes (IEL) expressing CD8αα. These lineages are shown to be essential for several aspects of immunity because their dysfunction or deficiency has been shown to lead to the development of autoimmune disease and cancers. Each of the above-mentioned cell types is characterized by a unique set of anatomical location, self-renewing capacity, surface phenotype and ligands.
For instance, B-1 cells are known to function as innate-like immunity effectors and are the key players in the early humoral response against bacteria, viruses, and certain parasites. Montecino-Rodriguez, Trends Immunol 27, 428-433. B1 cells are located mainly in the peritoneal and pleural cavities, and express high levels of surface IgM and low levels of IgD, CD23, and B220. They are thought to be the primary antibody producers in response to T cell-independent type 2 antigens, such as capsular polysaccharides on bacteria. Importantly, natural antibodies produced by B1 cells also bind to self-antigens, and this property could explain why B1 cells are often associated with autoimmune diseases in mice and humans.
Another example of B cells that play an important role in T cell-independent antibody response is MZ B cells. Viau and Zouali, Clin Immunol 114, 17-26. They are located at the junction of white and red pulp and have a surface phenotype distinct from other spleen B cells. MZ B cells respond vigorously to blood-borne infections, and play a role in host survival of infection by encapsulated bacteria.
A group of unconventional T cells that possess properties of both the innate and adaptive systems are the IEL cells. This subtype exclusively expresses CD8αα; however, they do not express either of the well-defined CD4 or CD8αβ TCR coreceptors, or several molecules found on most other T lymphocytes, such as CD2, CD28, and CD 90.
MicroRNA (miRNA) represent a newly discovered class of endogenous ˜22-nt RNAs encoded by biological species. Owing to their ability to post-transcriptionally regulate expression of nearly any target gene, miRNA have been implicated in a variety of processes in plants and animals, and have been shown to be involved in development, apoptosis, signal transduction, fat metabolism, insulin secretion, viral infection, and potentially many other processes. Bartel, Cell 116, 281-297. A growing body of evidence suggests that miRNAs play an important role in all aspects of immune system development and function from driving differentiation of certain cell lineages to fine-tuning of immune response to antigen. Fontana, Nat Cell Biol 9, 775-787; Li, Cell 129, 147-161.
Inflammation is a highly complex defense reaction of the host in response to an invading pathogen or injury, which when not resolved swiftly can result in quite severe pathological consequences. The importance of timely resolution of inflammatory reaction is underscored by the number of diseases where a failure to terminate inflammatory process is the main driving force, like rheumatoid arthritis, septic shock, inflammatory bowel disease and multiple sclerosis. In addition, there is mounting evidence that sustained inflammation is linked to various human cancers.
MicroRNAs have been shown to be involved in regulation of the innate immune response, and miRNAs that play a role in the mammalian response to microbial infection have been identified. Taganov, Proc Natl Acad Sci USA 103, 12481-12486.